Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin

AbstractThe establishment of relative size of organs and structures is paramount for attaining final form and function of an organism. Importantly, variation in the proportions of structures frequently underlies adaptive change in morphology in evolution and maybe a common mechanism underlying selection. However, the mechanism by which growth is integrated within tissues during development to achieve proper proportionality is poorly understood. We have shown that signaling by potassium channels mediates coordinated size regulation in zebrafish fins. Recently, calcineurin inhibitors were shown to elicit changes in zebrafish fin allometry as well. Here, we identify the potassium channelkcnk5bas a key player in integrating calcineurin’s growth effects, in part through regulation of the cytoplasmic C-terminus of the channel. We propose that the interaction between Kcnk5b and calcineurin acts as a signaling node to regulate allometric growth. Importantly, we find that this regulation is epistatic to inherent mechanisms instructing overall size as inhibition of calcineurin is able to bypass genetic instruction of size as seen insofand wild-type fins, however, it is not sufficient to re-specify positional memory of size of the fin. These findings integrate classic signaling mediators such as calcineurin with ion channel function in the regulation of size and proportion during growth.</jats:p

Bioelectric Signaling Regulates Size in Zebrafish Fins

The scaling relationship between the size of an appendage or organ and that of the body as a whole is tightly regulated during animal development. If a structure grows at a different rate than the rest of the body, this process is termed allometric growth. The zebrafish another longfin (alf) mutant shows allometric growth resulting in proportionally enlarged fins and barbels. We took advantage of this mutant to study the regulation of size in vertebrates. Here, we show that alf mutants carry gain-of-function mutations in kcnk5b, a gene encoding a two-pore domain potassium (K+) channel. Electrophysiological analysis in Xenopus oocytes reveals that these mutations cause an increase in K+ conductance of the channel and lead to hyperpolarization of the cell. Further, somatic transgenesis experiments indicate that kcnk5b acts locally within the mesenchyme of fins and barbels to specify appendage size. Finally, we show that the channel requires the ability to conduct K+ ions to increase the size of these structures. Our results provide evidence for a role of bioelectric signaling through K+ channels in the regulation of allometric scaling and coordination of growth in the zebrafish

Identification of a Novel Signaling Pathway and Its Relevance for GluA1 Recycling

We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P2. In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P2 in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory

What's in a name?: a discussion paper on the labels and location of self-organising community groups, with particular reference to mental health and Black groups

This article discusses the labelling and location of self-organising community groups – ‘self-help’, ‘peer support’ and ‘service user’. It notes the increasingly close relationship between these groups and statutory authorities, and how this relationship may put the benefits of the groups at risk. Historical, cultural and social factors are discussed to help explain differences and separate developments within African, Caribbean and other Black communities

Inequalities in health and community-oriented social work: lessons from Cuba?

Social justice is, as the World Health Organization Commission on Social Determinants of Health (WHO CSDH, 2008) reminds us, ‘a matter of life and death’. While the stark differences in mortality rates and life expectancy between rich and poor countries might be the most obvious example of this, it is also true that ‘Within countries, the differences in life chances are dramatic and are seen in all countries – even the richest’ (WHO CSDH, 2008: 26). As the Commission demonstrates, the roots of these inequities lie in social conditions, suggesting an important role for social work in this area. Unfortunately, the Commission says very little about the type of social work that might be appropriate: nevertheless, the report does provide fresh impetus to the debate about what social workers might contribute to tackling health inequalities. In this article, we suggest that a community-oriented approach to social work is required. In making a case for this, we review the progress of the government’s drive to reduce inequalities in England,1 arguing that this has, thus far, been largely unsuccessful because it has primarily been pursued through health-care services, while addressing the wider (social) determinants of health has been a secondary consideration. In contrast, we offer the example of Cuban community-oriented social work (COSW) which has helped maintain population health at a level that stands comparison with much wealthier nations, despite the hardships and inequalities which followed economic collapse in the 1990s. In many ways the Cuban situation is unusual, perhaps unique, so we are not arguing that Cuban social work methods can be readily transferred. Rather, we suggest that, in the neglected field of tackling health inequalities, social workers can learn from the general approach taken in Cuba. To establish the context of this discussion, we begin by defining key concepts: COSW itself, health inequalities and inequity, the health gap and the health gradient

Community participation and recovery for mental health service users: An action research inquiry

Introduction: The social inclusion of individuals with mental health problems is an issue for mental health services, for the individuals who experience stigma, discrimination and exclusion, and for society at large. To develop community-orientated services that are capable of promoting inclusion it will, therefore, be advantageous to all parties to understand what service users find most helpful. Method: A 2-year action research project explored the recovery journeys of a group of assertive outreach service users who had progressed from being socially excluded and occupationally deprived to being participants in their local communities. The research aimed to understand how these outcomes were produced and to use this knowledge to inform local service development. Findings: This paper focuses on eight qualitative interviews, where service users recounted their stories of community participation and inclusion. The findings show how assertive outreach practitioners harnessed occupation as a basis for building relationships between practitioners and service users, and how this became a conduit towards participation in the mainstream community. Conclusion: Facilitating engagement in community-based occupations through creative collaboration helped participants reconnect with cherished roles, achieve long-standing goals and develop feelings of self-efficacy, belonging and wellbeing.© The College of Occupational Therapists Ltd

Non-equivalent role of TM2 gating hinges in heteromeric Kir4.1/Kir5.1 potassium channels

Comparison of the crystal structures of the KcsA and MthK potassium channels suggests that the process of opening a K+ channel involves pivoted bending of the inner pore-lining helices at a highly conserved glycine residue. This bending motion is proposed to splay the transmembrane domains outwards to widen the gate at the “helix-bundle crossing”. However, in the inwardly rectifying (Kir) potassium channel family, the role of this “hinge” residue in the second transmembrane domain (TM2) and that of another putative glycine gating hinge at the base of TM2 remain controversial. We investigated the role of these two positions in heteromeric Kir4.1/Kir5.1 channels, which are unique amongst Kir channels in that both subunits lack a conserved glycine at the upper hinge position. Contrary to the effect seen in other channels, increasing the potential flexibility of TM2 by glycine substitutions at the upper hinge position decreases channel opening. Furthermore, the contribution of the Kir4.1 subunit to this process is dominant compared to Kir5.1, demonstrating a non-equivalent contribution of these two subunits to the gating process. A homology model of heteromeric Kir4.1/Kir5.1 shows that these upper “hinge” residues are in close contact with the base of the pore α-helix that supports the selectivity filter. Our results also indicate that the highly conserved glycine at the “lower” gating hinge position is required for tight packing of the TM2 helices at the helix-bundle crossing, rather than acting as a hinge residue

Wintering grounds, population size and evolutionary history of a cryptic passerine species from isotopic and genetic data

Cryptic species pose a particular challenge to biologists in the context of life history investigations because of the difficulty in their field discrimination. Additionally, there is normally a lag in their widespread acceptance by the scientific community once they are formally recognised. These two factors might constrain our ability to properly assess the conservation status of the different species conforming a cryptic complex. In this study, we analysed isotopic and genetic data to shed light into the still unclear wintering grounds, population size and evolutionary history of the Iberian chiffchaff Phylloscopus ibericus, a species included within the common chiffchaff Phylloscopus collybita until two decades ago due to their phenotypic similarity. We used molecular methods to identify spring-migrating Phylloscopus species captured in northern Iberia, and by comparing the Hydrogen isotopic ratios of their claw tips (δ2Hc; which would reflect the signatures of their wintering grounds), we detected that δ2Hc values of Iberian chiffchaffs were similar to willow warblers (Phylloscopus trochilus; a renowned trans-Saharan migrant), and higher than common chiffchaffs (mostly a pre-Saharan migrant). These results strongly support the idea that Iberian chiffchaffs winter in tropical Africa. We additionally reconstructed the phylogeny and evolutionary history of the Iberian chiffchaff's clade using mitochondrial and nuclear markers. Our results revealed relatively high values of nucleotide diversity (and, hence, high Ne) for the species that were greater than the values of the common/Iberian most recent common ancestor. This suggests that the Iberian chiffchaff did not experience strong bottlenecks after diverging from the common chiffchaff approximately one million years ago. Ultimately, our study provides another illustrative example of how isotopic and genetic analysis tools can help to enhance our understanding of avian ecology and evolution.Depto. de Biodiversidad, Ecología y EvoluciónFac. de Ciencias BiológicasTRUEpu

The Sparrow Question: Social and Scientific Accord in Britain, 1850-1900.

During the latter-half of the nineteenth century, the utility of the house sparrow (Passer domesticus) to humankind was a contentious topic. In Britain, numerous actors from various backgrounds including natural history, acclimatisation, agriculture and economic ornithology converged on the bird, as contemporaries sought to calculate its economic cost and benefit to growers. Periodicals and newspapers provided an accessible and anonymous means of expression, through which the debate raged for over 50 years. By the end of the century, sparrows had been cast as detrimental to agriculture. Yet consensus was not achieved through new scientific methods, instruments, or changes in practice. This study instead argues that the rise and fall of scientific disciplines and movements paved the way for consensus on "the sparrow question." The decline of natural history and acclimatisation stifled a raging debate, while the rising science of economic ornithology sought to align itself with agricultural interests: the latter overwhelmingly hostile to sparrows